The most recent data came from NSABP B-15, which compared the
combination of doxorubicin (Adriamycin) and cyclophosphamide (AC)
(alone or followed by CMF) against CMF (cyclophosphamide,
methotrexate, fluorouracil). The findings essentially confirmed data
from the earlier B-11 trial, which evaluated the effect of adding
doxorubicin to an older breast cancer chemotherapy regimen in
patients with node-positive, ER-negative disease (J Natl Cancer Inst
90:1361-1370, 1998).

The overall results of B-15 showed no outcome differences among the
three regimens, said Dr. Paik, a pathologist at Allegheny University
of the Health Sciences, Pittsburgh, and director of the NSABP
Pathology Section. However, an analysis of the 29% of patients who
overexpressed HER-2 revealed a clear trend favoring the
doxorubicin-containing regimen with respect to disease-free and
overall survival.

The B-15 study involved 2,295 patients, 2,034 of whom were included
in the analysis. The study population comprised 689 patients
randomized to the AC regimen, 679 randomized to AC followed by CMF,
and 666 randomized to CMF. Dr. Paik said that 599 patients were
positive for HER-2.

HER-2-positive patients treated with CMF had a relative risk of 1.24
for disease-free survival, compared with 0.99 for the AC cohort. For
overall survival, CMF patients had a relative risk of 1.45 vs 1.05
for patients treated with the AC regimen. A similar pattern was
observed in patients who received AC followed by CMF, Dr. Paik said.
Their relative risk for disease-free survival was 1.12 and for
overall survival, 1.04.

In patients treated with AC or AC followed by CMF,
overexpression of HER-2 was prognostic with a relative risk near 1,
which tells us that the addition of Adriamycin somehow changes the
natural history of patients who are HER-2 positive, Dr. Paik
said. There was no difference in relative risk for
HER-2-negative patients. The reduction in risk was seen only in HER-2-positive
patients. We observed the same pattern of benefit whether we
included or excluded second primary cancers or contralateral breast cancers.

Confirms B-11 Results

The B-15 data confirm an analysis of B-11, which randomized patients
to the combination of L-phenylalanine mustard (melphalan) and
fluorouracil, with or without doxorubicin (PF or PAF). Of 638
evaluable cases (ie, those with archived stained sections of the
primary tumor), 239 were positive for HER-2 overexpression.

HER-2-positive patients randomized to the doxorubicin-containing
regimen (PAF) had a relative risk of 0.58 for recurrence-free
survival, 0.74 for disease-free survival, and 0.66 for overall
survival, compared with patients in the PF cohort. In contrast,
HER-2-negative patients treated with PAF had no advantage over PF
patients, as the relative risk approached 1.00 for all outcome parameters.

The B-15 data are consistent with those from B-11, Dr.
Paik said. Because of the consistencies, I think the B-15 data
can be regarded as a confirmation of B-11. I personally conclude that
AC can be used safely in HER-2-positive patients and does not add
harm over CMF when given to HER-2-negative patients.

A preliminary analysis of data from NSABP B-14, which evaluated the
effect of tamoxifen (Nolvadex) on survival parameters, has
demonstrated that HER-2 status does not predict outcome with
tamoxifen, Dr. Paik added.

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